Synthetic milk compositions comprising polyunsaturated fatty acids (pufas) for promoting the healthy establishment of cognitive function in male and female infant and children

ABSTRACT

The invention concerns synthetic nutritional formulations, particularly milk based compositions, for infants and children. The compositions are especially adapted to the gender of the child. The invention further relates to administration of these compositions for promoting the healthy establishment of cognitive function in infant boys and girls or in young boys and girls.

TECHNICAL FIELD

The invention concerns synthetic nutritional formulations, particularlymilk based compositions, for infants and children. The compositions areespecially adapted to the gender of the child. The invention furtherrelates to administration of these compositions for promoting thehealthy establishment of cognitive function in infant boys and girls orin young boys and girls.

BACKGROUND OF THE INVENTION

Nervous system development and maturation is a highly complex biologicalphenomenon that involves a number of physiological processes. Thenervous system develops during gestation and then refines to a mature,functional network during the post natal period.

Immaturity or delayed maturation of the cerebral cortex may lead todelayed and/or impaired learning ability, loss of, or poor developmentof higher reasoning, concentration difficulties, delay in languagedevelopment, memory and executive function problems, decreasedintelligence, and thus, poor mental performance. Other disorders, suchas mood disorders and disorders linked to the inability to communicateand socialize normally (for example, autism, including Asperger'ssyndrome), may also result.

This can be observed in infants such as:

-   -   Preterm infants, low birth weight (<2500 g), very low and        extremely low birth weight infants (<1500 g), and in small for        gestational age infants [Allen, M. C. (2008); Neurodevelopmental        outcomes of preterm infants, Curr. Opin Neurol., 21(2): 123-8].    -   Premature or term-born infants having experienced an        intrauterine growth retardation (IUGR) that occurred following        any adverse events during the gestation (smoking of the mother,        medication of the mother, low placenta quality, abnormal        placenta positioning, malnutrition of the mother and the foetus,        excessive stress/anxiety of the mother, etc); [Gregory, A. et        al. (2008); Intrauterine Growth Restriction Affects the Preterm        Infant's Hippocampus, Pediatric Research, 63(4): 438-443].    -   Any neonate and young infant showing nervous system growth        retardation following, for example, hypoxemia-ischemia at birth,        or any other adverse event [Barrett, R. D. et al. (2007);        Destruction and reconstruction: hypoxia and the developing        brain, Birth Defects Res. C. Embryo Today, 81: 163-76].

It is known that nutrition plays an important role in neuronalmaturation in the brain (reviewed in [Huppi, P. S. (2008); Nutrition forthe Brain, Pediatric Research, 63(3): 229-231]). Specifically, clinicalstudies have shown that essential fatty acids are crucial to ensurefoetal and postnatal brain development [Chang, C. Y. et al. (2009);Essential fatty acids and human brain, Acta Neurol. Taiwan, 18(4):231-41]; [Alessandri, J. M. et al. (2004); Polyunsaturated fatty acidsin the central nervous system: evolution of concepts and nutritionalimplications throughout life, Reprod. Nutr. Dev., 44(6): 509-38].

The consequences of malnutrition can be irreversible and may includepoor cognitive development, educability, and thus future economicproductivity [Horton, R; (2008) The Lancet, Vol. 371, Issue 9608, page179; [Laus, M. F. et al. (2011); Early postnatal protein-caloriemalnutrition and cognition: a review of human and animal studies, Int.J. Environ. Res. Public Health., 8(2): 590-612].

Thus, oral interventions are an appropriate way to positively impact onthe development of the nervous system, so as to promote the healthyestablishment of cognitive function and mental performance in infants oryoung children.

In general, human breast milk represents the uncontested gold standardin terms of infant nutrition. In particular, early breastfeeding and ahigher protein intake have been shown beneficial to neuronal maturationin infants (reviewed in [Huppi, P. S. (2008)]. However, in some casesbreastfeeding is inadequate or unsuccessful for medical reasons orbecause of mother choice not to breastfeed. Infant formulae have beendeveloped for these situations.

One approach to designing infant formula has been to try to designformulae that resemble breast milk. However, the complexity of thecomposition of human milk, much about which is still unknown, makes thisapproach technically very challenging.

In humans during pregnancy, hormones such as estrogen, progesterone andprolactin lead to glandular proliferation and differentiation, whichprepares the mammary glands for milk synthesis. After the birth, theprimed mammary glands synthesize milk which is likely to vary accordingto genetic, environmental, behavioral, dietary and other physiologicalfactors. More specifically, the maternal dietary influence on milkcomposition is varied and is nutrient specific.

To add to this complexity, human lactation is dynamic, occurring instages of lactation, changing from early carbohydrate-rich diluted milkto lipid and protein enriched, energy-dense milk at later stages (after30 days). In humans, early milk or colostrum (1-5 days) is known to berich in immune factors and mature milk in energy density. Furthermore,Powe and associates [Powe C. E. et al. (2010); Infant sex predictsbreast milk energy content, American journal of human biology, 22:50-54]have recently reported differences in energy content based on the genderof the new born infant. Milk secreted from the mothers of male infantswas reported to be 25% greater in energy content when compared with themilk of mothers of female infants.

As well as depending on the maturity of lactation, it has beendemonstrated that many nutrients in breast milk are dependent on thetime of the day the milk is sampled (diurnal variations), whether only apart of feeding (pre-, mid-, or hind-milk) or whole breast milk wascollected, whether left or the right breast was drained [Jensen R G.,(1999), Lipids in Human Milk, Lipids 34, 1243-1271]. In terms of humanmilk characterization, whereas there are many reports in the prior arton the relative amounts of nutrients, including fatty acids andphospholipids (expressed as g per 100 g of phospholipids) in breast milk[Sala-Vila A., et al (2005), Lipid composition in human breast milk fromGranada (Spain): Changes during lactation, Nutrition 21, 467-473], thereis very little data on the absolute quantities (for example ofphospholipids). Thus, the level of intake by the infant of the nutrientsremains largely unknown.

Given the complexity of breast milk composition, it remains verychallenging to develop synthetic nutritional compositions based onbreast milk composition.

There is a need to provide nutritional interventions that meet thenutritional needs of infants and young children. In particular, there isa need to provide nutritional interventions that are adapted to thedistinct nutritional needs of male and female infants and youngchildren.

There is a need to provide compositions that promote and support thehealthy establishment of cognitive function, during the early phases ofnewborn life, when the nervous system is rapidly maturing.

The present inventors have designed synthetic nutritional compositionsthat are especially adapted to meet the needs of male and female infantsand young children. The compositions of the present invention have beendesigned to ensure the healthy establishment of cognitive function.

SUMMARY OF THE INVENTION

The present invention concerns synthetic nutritional formulations forinfants and young children, meaning in the context of the invention, upto the age of 36 months. The compositions are especially adapted to thegender of the child. The invention further relates to administration ofthese compositions for promoting the healthy establishment of cognitivefunction in infant boys and girls or in young boys and girls.

In a first aspect of the invention, there is provided a syntheticnutritional composition especially adapted to the nutritional needs of amale infant or young child. The composition comprises:

-   -   a. 600-810 mg/100 ml linoleic acid,    -   b. 42-52 mg/100 ml α-linolenic acid and    -   c. 720-925 mg/100 ml total polyunsaturated fatty acids.

In a preferred embodiment, the composition may also comprise any one ora mixture of:

-   -   d. 0.18-0.50 mg/100 ml of monosialoganglioside-3 (GM3),    -   e. 0.4-0.7 mg/100 ml of GM3+disialogangliosides 3 (GD3) and    -   f. 8.0-10.4 mg/100 ml of sphingomyelin.

In another preferred embodiment, the composition may also comprise oneor a mixture of phospholipids g.-j.:

-   -   g. 4.7-5.9 mg/100 ml of phosphatidylcholine,    -   h. 6.3-10 mg/100 ml of phosphatidylethanolamine,    -   i. 1-2 mg/100 ml of phosphatidylinositol and    -   j. 0.7-1.1 mg/100 ml of phosphatidylserine.

In another preferred embodiment, the composition additionally comprises:

-   -   k. 20 to 30 mg/100 ml of phospholipids.

In another preferred embodiment, the composition is especially adaptedto the nutritional needs of a male infant less than 3 months old. Thiscomposition comprises:

-   -   a. 600-740 mg/100 ml linoleic acid,    -   b. 42-52 mg/100 ml α-linolenic acid and    -   c. 720-880 mg/100 ml total polyunsaturated fatty acids.

The composition may additionally comprise any one or more of thecomponents d.-k. indicated above.

In another preferred embodiment, the composition is especially adaptedto the nutritional needs a male infant or child older than 3 months oldand younger than 36 months. This composition comprises:

-   -   a. 660-810 mg/100 ml linoleic acid,    -   b. 42-52 mg/100 ml α-linolenic acid and    -   c. 760-925 mg/100 ml total polyunsaturated fatty acids.

The composition additionally comprises one or more of the following ofcomponents in the following quantities:

-   -   d. 0.35-0.50 GM3,    -   e. 0.4-0.7 mg/100 ml of GM3+GD3,    -   f. 8.5-10.4 mg/100 ml sphingomyelin,    -   g. 4.7-5.9 mg/100 ml phosphatidylcholine,    -   h. 8-9.8 mg/100 ml of phosphatidylethanolamine,    -   i. 1.62-2 mg/100 ml of phosphatidylinositol,    -   j. 0.7-1.1 mg/100 ml of phosphatidylserine and    -   k. 24-30 mg/100 ml total phospholipids.

In a second aspect of the invention, there is provided a syntheticnutritional composition especially adapted to the nutritional needs of afemale infant or young child comprising:

-   -   a. 410-580 mg/100 ml linoleic acid,    -   b. 26-30 mg/100 ml α-linolenic acid and    -   c. 510-680 mg/100 ml total polyunsaturated fatty acids.

In a preferred embodiment of this second aspect of the invention thesynthetic nutritional composition also comprises any one or a mixtureof:

-   -   d. 0.22-0.40 mg/100 ml of GM3,    -   e. 0.4-0.6 mg/100 ml of GM3+GD3 and    -   f. 7-9 mg/100 ml of sphingomyelin.

In another preferred embodiment of this second aspect of the invention,the synthetic nutritional composition also comprises any one or amixture of phospholipids g.-j.:

-   -   g. 5-6.4 mg/100 ml of phosphatidylcholine,    -   h. 5.8-8 mg/100 ml of phosphatidylethanolamine,    -   i. 0.8-1.7 mg/100 ml of phosphatidylinositol and    -   j. 0.5-1 mg/100 ml of phosphatidylserine.

In another preferred embodiment of the second aspect of the invention,the synthetic nutritional composition also comprises:

-   -   k. 19.5 to 25 mg/100 ml of phospholipids.

In another preferred embodiment, the composition is especially adaptedto the nutritional needs of a female infant younger than 3 months old.This composition is according to the second aspect of the invention, andcomprises:

-   -   a. 410-510 mg/100 ml linoleic acid,    -   b. 26-30 mg/100 ml α-linolenic acid and    -   c. 510-60 mg/100 ml total polyunsaturated fatty acids.

In another preferred embodiment, the composition for females isespecially adapted to the nutritional needs of a female infant or childolder than 3 months old and younger than 36 months. This composition isaccording to the second aspect of the invention, and comprises:

-   -   a. 470-580 mg/100 ml linoleic acid,    -   b. 26-30 mg/100 ml α-linolenic acid and    -   c. 540-680 mg/100 ml total polyunsaturated fatty acids.

The latter composition is especially adapted to the nutritional needs ofa female infant or child older than 3 months old and younger than 36months and may also comprise one or more of the following of componentsd to k.:

-   -   d. 0.3-0.4 GM3,    -   e. 0.4-0.6 mg/100 ml of GM3+GD3,    -   f. 7.1-8.7 mg/100 ml sphingomyelin,    -   g. 5.2-6.4 mg/100 ml phosphatidylcholine,    -   h. 6.4-8 mg/100 ml of phosphatidylethanolamine,    -   i. 1.35-1.7 mg/100 ml of phosphatidylinositol,    -   j. 0.5-1 mg/100 ml of phosphatidylserine and    -   k. 19.8-24.2 mg/100 ml total phospholipids.

In a third aspect of the invention, there is provided a set of twosynthetic nutritional compositions, wherein the first composition isespecially adapted to the nutritional needs of a male infant or child,as described according to the first aspect of the invention. The secondcomposition as described according to the first aspect of the inventionis especially adapted to the nutritional needs of a female infant orchild.

The compositions according to the invention are especially adapted topromote the healthy establishment of cognitive function in infants andyoung children. According to a preferred embodiment of the invention,the compositions according to the first aspect of the invention and thefirst composition in the sets of nutritional compositions according tothe third aspect of the invention are targeted to promote the healthyestablishment of cognitive function in male children. According toanother preferred embodiment of the invention, the compositionsaccording to the second aspect of the invention and the secondcomposition in the sets of nutritional compositions according to thethird aspect of the invention are targeted to promote the healthyestablishment of cognitive function in female children.

According to preferred embodiments of the invention, compositionsspecifically adapted to male infants that are less than 3 months old aretargeted to promote the healthy establishment of cognitive function inthese infants.

According to preferred embodiments of the invention, compositionsspecifically adapted to male infants and young children that are morethan 3 months old are targeted to promote the healthy establishment ofcognitive function in these infants.

According to preferred embodiments of the invention, compositionsspecifically adapted to female infants and that are less than 3 monthsold are targeted to promote the healthy establishment of cognitivefunction in these infants.

According to other preferred embodiments of the invention, compositionsspecifically adapted to female infants and young children and that aremore than 3 months old are targeted to promote the healthy establishmentof cognitive function in these infants.

In a preferred embodiment, the synthetic nutritional compositions of theinvention may be an infant formula in the form of a powder, liquid orconcentrated liquid, or is a human milk fortifier, or a growing-up milk.In a preferred embodiment, the infant formula is a cow's milk whey-basedformula.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1-3 show the results of the analysis of nutrients in the breastmilk of 50 mothers in trial detailed in Example 1. Samples were taken at30, 60 and 120 days post-partum. Quantities were measured in mg/100 ml.The measurements of milk of mothers to boys are shown with a dashedline, while the solid line shows the measurements of milk of mothers togirls. The P[gender] value relates to the differences in milk withrespect to the sex of the baby. The P[age] values are differences ingender with respect to time; P[age] is a P value considering a linearmodel and P[age²] using a quadratic model. FIG. 1A shows linoleic acid,FIG. 1B shows alpha-linolenic acid, and FIG. 1C total polyunsaturatedfatty acids (PUFA). FIG. 2A shows monosialoganglioside 3 (GM3), FIG. 2Bshows GM3+disialogangliosides 3 (GD3), FIG. 2C shows sphingomyelin (SM).FIG. 3A shows phosphatidylcholine, FIG. 3B showsphosphatidylethanolamine, FIG. 3C shows phosphatidylinositol, FIG. 3Dshows phosphatidylserine and 3E shows total phospholipids.

DETAILED DESCRIPTION

For a complete understanding of the present invention and the advantagesthereof, reference is made to the following detailed description of theinvention.

It should be appreciated that various embodiments of the presentinvention can be combined with other embodiments of the invention andare merely illustrative of the specific ways to make and use theinvention and do not limit the scope of the invention when taken intoconsideration with the claims and the following detailed description.

In the present description, the following words are given a definitionthat should be taken into account when reading and interpreting thedescription, examples and claims.

DEFINITIONS

Infants: according to the Commission Directive 2006/141/EC of 22 Dec.2006 on infant formulae and follow-on formulae, article 1.2 (a), theterm “infants” means children under the age of 12 months.

Young Children: according to the Commission Directives 2006/141/EC of 22Dec. 2006 and/or 91/321/EEC of 14 May 1991 on infant formulae andfollow-on formulae, article 1.2 (b), the term “young children” meanschildren aged between one and three years.

Infant formulae: according to the Commission Directives 2006/141/EC of22 Dec. 2006 and/or 91/321/EEC of 14 May 1991 on infant formulae andfollow-on formulae, article 1.2 (c), the term “infant formulae” meansfoodstuffs intended for particular nutritional use by infants during thefirst four to six months of life and satisfying by themselves thenutritional requirements of this category of persons. It has to beunderstood that infants can be fed solely with infant formulas, or thatthe infant formula can be used by the carer as a complement of humanmilk. It is synonymous to the widely used expression “starter formula”.

Follow-on formulae: according to the Commission Directives 2006/141/ECof 22 Dec. 2006 and/or 91/321/EEC of 14 May 1991 on infant formulae andfollow-on formulae, article 1.2 (d), the term “follow-on formulae” meansfoodstuffs intended for particular nutritional use by infants aged overfour months and constituting the principal liquid element in aprogressively diversified diet of this category of persons.

Growing-up milk: milk-based nutritional composition especially adaptedto a child of between one year and three years old.

Human Milk fortifier: Nutritional composition for infants or youngchildren intended to be added to or diluted with human milk.

The term “hypoallergenic composition” means a composition which isunlikely to cause allergic reactions.

The term “sialylated oligosaccharide” means an oligosaccharide having asialic acid residue.

The term “fucosylated oligosaccharide” means an oligosaccharide having afucose residue.

The term “prebiotic” means non-digestible carbohydrates thatbeneficially affect the host by selectively stimulating the growthand/or the activity of healthy bacteria such as bifidobacteria in thecolon of humans [Gibson G R, Roberfroid M B. Dietary modulation of thehuman colonic microbiota: introducing the concept of prebiotics. J Nutr.1995; 125:1401-12].

The term “probiotic” means microbial cell preparations or components ofmicrobial cells with a beneficial effect on the health or well-being ofthe host. [Salminen S, Ouwehand A. Benno Y. et al. “Probiotics: howshould they be defined” Trends Food Sci. Technol. 1999:10 107-10].

An “allergy” is an allergy which has been detected by a medical doctorand which can be treated occasionally or in a more durable manner. A“food allergy” is an allergy with respect to a nutritional composition.

All percentages are by weight unless otherwise stated.

As used in this specification, the words “comprises”, “comprising”, andsimilar words, are not to be interpreted in an exclusive or exhaustivesense. In other words, they are intended to mean “including, but notlimited to”.

Any reference to prior art documents in this specification is not to beconsidered an admission that such prior art is widely known or formspart of the common general knowledge in the field.

The present inventors have carried out a major study on breast milkcomposition. This study involved both developing advanced analyticaltechnologies to analyze milk samples and performing a longitudinalclinical trial with human milk sampling at 30, 60 and 120 dayspost-partum (see Example 1). The milk samples were quantitativelyanalyzed for macronutrients, fatty acids, phospholipids andgangliosides. The inventors have surprisingly found very significantdifferences, between milk of mothers of male infants compared to that offemale infants, not only in energy (differences are greater thanpreviously reported), but also in the quantities of a number of fattyacids, phospholipids and gangliosides. In some cases, this differencebetween male and female destined milk varied over time (between 0-120days).

The results of this trial indicated surprisingly significant differencesin the levels of linoleic acid (LA), α-linolenic acid (ALA),monosialoganglioside 3 (GM3), the sum of GM3 and disialogangliosides 3(GD3), sphingomyelin, phosphatidylcholine, phosphatidylethanolamine,phosphatidylinositol, phosphatidylserine and total phospholipids forboys and girls (see Table 2 and FIGS. 1-3).

Based upon the results of this study, the inventors have designedcompositions that are especially adapted to meet the nutritional needsof male and female infant and young children. To the inventor'sknowledge, to date, no gender specific formulations for infants or youngchildren are known.

The Compositions According to the Invention:

The compositions of the invention are designed to meet the nutritionalneeds of male and female infants and young children. The compositionsensure development of optimal cognitive function in these infants oryoung children.

The synthetic nutritional compositions of the invention are designed forconsumption by children from birth to three years old. They arespecifically designed to be gender specific. In certain embodiments,they are also age specific, being designed for infants younger thanthree months old, or older than three months, but less than 36 months.

The synthetic nutritional compositions of the invention may be an infantformula in the form of a powder, liquid or concentrated liquid. Theinfant formula may be based on a cow's milk, goat's milk or buffalomilk. The infant formula may be a starter formula for infants that areless than six months old or a follow-on formula for infants that aremore than 6 months old. The composition of the invention may be agrowing up milk, or a human milk fortifier. In a preferred embodiment,the composition may be cow's milk whey based infant formula. The formulamay also be a hypoallergenic (HA) formula in which the cow milk proteinsare (partially or extensively) hydrolysed. The formula may also be basedon soy milk or a non-allergenic formula, for example one based on freeamino acids.

The nutritional compositions of the invention contain specificquantities of essential fatty acids, specifically linoleic acid (LA),α-linolenic acid (ALA) and polyunsaturated fatty acids (PUFA5). Thespecific quantities of these nutrients are gender specific. In general,the compositions for males contain higher quantities of fatty acidscompared to those for females. Quantities of the gangliosidesmonosialoganglioside-3 (GM3) as well as the sum of GM3 anddisialogangliosides 3 (GD3) also vary depending on whether thecomposition is for a male or female. Quantities of sphingomyelin,phospholipids phosphatidylcholine, phosphatidylethanolamine,phosphatidylinositol and phosphatidylserine also vary for male andfemale destined compositions. The total number of phospholipids variesalso. All of the latter components—essential fatty acids, sphingomyelinand phospholipids, are known to be involved in cognitive functiondevelopment.

Thus, the composition according to one embodiment of the invention isespecially adapted to the nutritional needs of a male infant or youngboy (up to the age of 36 months), and comprises:

-   -   a. 600-810 mg/100 ml, preferably 670-730 mg/100 ml linoleic acid        (LA),    -   b. 42-52 mg/100 ml, preferably 45-47 mg/100 ml α-linolenic acid        (ALA) and    -   c. 720-925 mg/100 ml, preferably 800-840 mg/100 ml total        polyunsaturated fatty acids (PUFA).

The quantities of all the nutrients expressed herein as mg/100 ml org/100 ml reflect the amounts of nutrients present in the final liquidproduct, to be consumed by the infant or young child. For example, thecomposition may be a powdered infant formula that is diluted with waterto give a final liquid product. The composition according to theinvention may also be a concentrated liquid that is diluted with waterto achieve the final liquid product. The composition of the inventionmay be a liquid product that is directly consumed by the infant or childas is. The composition according to the invention may be a human milkfortifier that is added to or diluted with human milk. In this case, theconcentration of the nutrients already present in the human milk (towhich the human milk fortifier is added) are to be taken as the averagevalues for lactating mothers that are known or predicted from publishedclinical data.

In another embodiment, the composition also comprises any one or amixture of:

-   -   d. 0.18-0.50 mg/100 ml, preferably 0.22-0.43 mg/100 ml of GM3,    -   e. 0.4-0.7 mg/100 ml, preferably 0.45-0.62 mg/100 ml of GM3+GD3        and    -   f. 8.0-10.4 mg/100 ml, preferably 8.9-9.4 mg/100 ml of        sphingomyelin.

In another embodiment, the composition may also comprise any one or amixture of the phospholipids g.-j.:

-   -   g. 4.7-5.9 mg/100 ml, preferably 5.3-6.1 mg/100 ml of        phosphatidylcholine,    -   h. 6.3-10 mg/100 ml, preferably 7.1-8.9 mg/100 ml of        phosphatidylethanolamine,    -   i. 1-2 mg/100 ml, preferably 1-1.2 mg/100 ml of        phosphatidylinositol and    -   j. 0.7-1.1 mg/100 ml, preferably 0.85-9.4 mg/100 ml of        phosphatidylserine.

In another embodiment, the composition comprises:

-   -   k. 20 to 30 mg/100 ml, preferably 24-26.3 mg/100 ml of        phospholipids.

Thus, the composition comprises a, b and c. It may further comprise anyone or a mixture of d to k. For example, the composition may comprise700 mg/100 ml LA, 46 mg/100 ml ALA, 840 mg/100 ml PUFA, 0.55 mg/100 mlGM3+GD3, and total phospholipids of 25 mg/100 ml.

For example, the composition may comprise 750 mg/100 ml LA, 44 mg/100 mlALA, 780 mg/100 ml PUFA, 0.30 mg/100 ml GM3, 5.8 mg/100 ml ofphosphatidylcholine, 8.5 mg/100 ml of phosphatidylethanolamine, 1.1mg/100 ml of phosphatidylinositol, 0.85 mg/100 ml of phosphatidylserine,9.2 mg/100 ml of sphingomyelin and total phospholipids of 24 mg/100 ml.

For example, the composition may comprise 770 mg/100 ml LA, 48 mg/100 mlALA, 8800 mg/100 ml PUFA, 0.40 mg/100 ml GM3, 0.20 mg/100 ml GD3, 9.0mg/100 ml of sphingomyelin and total phospholipids of 24 mg/100 ml.

Based on the results of the clinical trial, detailed in Example 1, theinventors have surprisingly discovered that the differences betweencertain nutrients in breast milk for boys and girls vary significantlywith time.

Thus, in another embodiment, the composition for male infants or youngchildren is especially adapted to the nutritional needs of a male infantof less than 3 months. This composition comprises:

-   -   a. 600-740 mg/100 ml, preferably 660-680 mg/100 ml linoleic        acid,    -   b. 42-52 mg/100 ml, preferably 47-45 mg/100 ml α-linolenic acid        and    -   c. 720-880 mg/100 ml, preferably 790-810 mg/100 ml total        polyunsaturated fatty acids.

The compositions may also comprise any one or a mixture of components d.to k., as detailed above for a composition especially adapted for a maleinfant or young boy.

For example, the composition may comprise 680 mg/100 ml LA, 48 mg/100 mlALA, 800 mg/100 ml PUFA, 0.30 mg/100 ml GM3, 5.8 mg/100 ml ofphosphatidylcholine, 8.5 mg/100 ml of phosphatidylethanolamine, 1.1mg/100 ml of phosphatidylinositol, 0.78 mg/100 ml of phosphatidylserine,9.2 mg/100 ml of sphingomyelin and total phospholipids of 24 mg/100 ml.

In another preferred embodiment, the composition for a male infant oryoung child is especially adapted to the nutritional needs a male infantor young child older than 3 months old and younger than 36 months.

This composition comprises:

-   -   a. 660-810 mg/100 ml, preferably 720-740 mg/100 ml linoleic        acid,    -   b. 42-52 mg/100 ml, preferably 47-45 mg/100 ml α-linolenic acid        and    -   c. 760-925 mg/100 ml, preferably 830-850 mg/100 ml total        polyunsaturated fatty acids.

In addition, the composition may also specifically comprise one or moreof the following of components in the following quantities:

-   -   d. 0.35-0.50 mg/ml, preferably 0.42-0.44 mg/100 ml GM3,    -   f. 8.5-10.4 mg/100 ml, preferably 9.2-9.6 mg/100 ml        sphingomyelin,    -   g. 4.7-5.9 mg/100 ml, preferably 5.2-5.4 mg/100 ml        phosphatidylcholine,    -   h. 8-9.8 mg/100 ml, preferably 8.8-9.0 mg/100 ml of        phosphatidylethanolamine,    -   i. 1.62-2 mg/100 ml, preferably 1.7-1.9 mg/100 ml of        phosphatidylinositol,    -   j. 0.7-1.1 mg/100 ml, preferably 0.85-0.94 mg/100 ml of        phosphatidylserine and    -   k. 24-30 mg/100 ml, preferably 26-27 mg/100 ml total        phospholipids.

For example, the composition may comprise 780 mg/100 ml LA, 48 mg/100 mlALA, 870 mg/100 ml PUFA, 0.43 mg/100 ml GM3, 5.6 mg/100 ml ofphosphatidylcholine, 8.8 mg/100 ml of phosphatidylethanolamine, 1.8mg/100 ml of phosphatidylinositol, 0.88 mg/100 ml of phosphatidylserine,9.2 mg/100 ml of sphingomyelin and total phospholipids of 27 mg/100 ml.

Furthermore, the inventors have designed nutritional compositionsspecifically adapted to meet the nutritional needs of female infants andyoung girls (up to the age of 3 years old). These compositions aredesigned to promote the healthy establishment of cognitive function infemale infants and young girls (up to the age of 3).

In an embodiment of the invention, these compositions comprise:

-   -   a. 410-580 mg/100 ml, preferably 460-525 mg/100 ml linoleic        acid,    -   b. 25-38 mg/100 ml, preferably 30-33 mg/100 ml α-linolenic acid        and    -   c. 510-680 mg/100 ml, preferably 570-610 mg/100 ml total        polyunsaturated fatty acids.

In a further embodiment of the invention, the synthetic nutritionalcomposition that is especially adapted to the nutritional needs of afemale infant or young child comprises, in addition to a.-c., any one ora mixture of:

-   -   d. 0.22-0.40 mg/100 ml, preferably 0.25-0.35 mg/100 ml of GM3,    -   e. 0.4-0.6 mg/100 ml, preferably 0.48 mg/100 ml of GM3+GD3 and    -   f. 7-9 mg/100 ml, preferably 7.9-8.1 mg/100 ml of sphingomyelin.

In a further embodiment of the invention, the synthetic nutritionalcomposition especially adapted for females also comprises any one or amixture of phospholipids g.-j.:

-   -   g. 5-6.4 mg/100 ml, preferably 5.8 mg/100 ml of        phosphatidylcholine,    -   h. 5.8-8 mg/100 ml, preferably 6.5-7.2 mg/100 ml of        phosphatidylethanolamine,    -   i. 0.8-1.7 mg/100 ml, preferably 1-1.5 mg/100 ml of        phosphatidylinositol,    -   j. 0.5-1 mg/100 ml, preferably 0.66-0.86 mg/100 ml of        phosphatidylserine.

In a further embodiment of the invention, the synthetic nutritionalcomposition especially adapted for females also comprises:

-   -   k. 19.5 to 25 mg/100 ml, preferably 22 mg/100 ml of        phospholipids.

In a preferred embodiment of the invention, the composition for femalesis especially adapted to the nutritional needs of a female infantyounger than 3 months old.

This composition comprises:

-   -   a. 410-510 mg/100 ml, preferably 450-470 mg/100 ml linoleic        acid,    -   b. 25-38 mg/100 ml, preferably 30-33 mg/100 ml α-linolenic acid        and    -   c. 510-680 mg/100 ml, preferably 560-580 mg/100 ml total        polyunsaturated fatty acids.

The components d. to k. may be present in the quantities indicated abovefor the compositions for females.

In another preferred embodiment, the composition for females isespecially adapted to the nutritional needs of a female infant or childolder than 3 months old and younger than 36 months. This compositioncomprises:

-   -   a. 470-580 mg/100 ml, preferably 520-540 mg/100 ml linoleic        acid,    -   b. 25-38 mg/100 ml, preferably 30-33 mg/100 ml α-linolenic acid        and    -   c. 540-680 mg/100 ml, preferably 600-620 mg/100 ml total        polyunsaturated fatty acids.

The latter composition may additionally comprise any one or more of thefollowing components:

-   -   d. 0.3-0.4 mg/100 ml, preferably 0.34-0.36 mg/100 ml GM3,    -   e. 0.4-0.6 mg/100 ml, preferably 0.48 mg/100 ml of GM3+GD3,    -   f. 7.1-8.7 mg/100 ml, preferably 7.8-8.0 mg/100 ml        sphingomyelin,    -   g. 5.2-6.4 mg/100 ml, preferably 5.7-5.9 mg/100 ml        phosphatidylcholine,    -   h. 6.4-8 mg/100 ml, preferably 7.1-7.3 mg/100 ml of        phosphatidylethanolamine,    -   i. 1.35-1.7 mg/100 ml, preferably 1.4-1.6 mg/100 ml of        phosphatidylinositol,    -   j. 0.5-1 mg/100 ml, preferably 0.66-0.86 mg/100 ml of        phosphatidylserine and    -   k. 19.8-24.2 mg/100 ml, preferably 21-23 mg/100 ml total        phospholipids.

For example, the composition may comprise 550 mg/100 ml LA, 48 mg/100 mlALA, 500 mg/100 ml PUFA, 0.35 mg/100 ml GM3, 5.6 mg/100 ml ofphosphatidylcholine, 7 mg/100 ml of phosphatidylethanolamine, 1.5 mg/100ml of phosphatidylinositol, 0.8 mg/100 ml of phosphatidylserine, 8.0mg/100 ml of sphingomyelin and total phospholipids of 22 mg/100 ml.

In a third aspect of the invention, there is provided a set of at leasttwo distinct synthetic nutritional compositions. Each set comprises afirst composition and second composition. The first composition is anyof the compositions described above that are especially adapted to thenutritional needs of a male infant or child. The second composition isany of the compositions described above that is especially adapted tothe nutritional needs of a female infant or child.

The first and second compositions are distinct in that they differ by atleast 10% in the quantity of at least one of the common components inthe two compositions chosen among a. to k.

The first and second compositions are or can be conditioned separately.The first and second compositions in the set are commercialized underthe same marketing concept umbrella. The first and second compositionsmay be then conditioned separately, or group together in another outercontainer, or packaging. The packaging may be for example simply a layeror plastic film, a bag, box, piece of foil, or other means to keep thefirst and second compositions grouped together.

The set of the invention can preferably be commercialized under the samemarketing concept (for example gender segmentation and/or specificadaptation of nutritional compositions for male and female infants orchildren).

The set may comprise additional third, fourth and fifth etc.compositions that are especially adapted to meet the nutritional needsof infants or young children that are for example, 3-6 months old 6-9months old or 9-12 months old. The set may also contain additionalcompositions that target in the same way children older than one year upto three years old.

Other Ingredients in the Compositions:

Other standard ingredients known to the skilled person for formulatingan infant formula, human milk fortifier or growing-up milk may also bepresent in the compositions of the invention.

The synthetic nutritional composition of the invention for male and thesynthetic nutritional composition of the invention for female maycomprise same or similar ingredients, such as oligosaccharides, lipids,prebiotics or probiotics (for example as indicated below). Preferablyhowever such ingredients may be different and particularly selected andadapted for the male and the female compositions. Preferably the dosageof each ingredient is adapted for the male and female compositions. Suchadaptation preferably provides each of the male and female compositionsthe best adapted nutritional content for addressing specific needs orhealth conditions of males and females. Such health conditions caninclude the optimum growth, the optimum gut development, the optimaldigestive function, the optimum immune functions or immune development,the optimum cognitive functions or development, or the optimumneurological development for the male and female infants.

The nutritional compositions of the invention may contain otheringredients which may act to enforce the technical effect of thecomponents a.-k.

Prebiotics:

The prebiotics that may be used in accordance with the present inventionare not particularly limited and include all food substances thatpromote the growth of probiotics or health beneficial micro-organisms inthe intestines. Preferably, they may be selected from the groupconsisting of oligosaccharides, optionally containing fructose,galactose, mannose; dietary fibers, in particular soluble fibers, soyfibers; inulin; or mixtures thereof. Preferred prebiotics arefructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS),isomalto-oligosaccharides (IMO), xylo-oligosaccharides (XOS),arabino-xylo oligosaccharides (AXOS), mannan-oligosaccharides (MOS),oligosaccharides of soy, glycosylsucrose (GS), lactosucrose (LS),lactulose (LA), palatinose-oligosaccharides (PAO),malto-oligosaccharides, gums and/or hydrolysates thereof, pectins and/orhydrolysates thereof.

In particular, the human milk oligosaccharides, for example sialylatedoligosaccharides, described in WO 2012/069416 published on May 31, 2012may be included in the composition according to the invention. Thelatter oligosaccharides may act in synergy with the essential fattyacids and phospholipids of the invention to promote the healthyestablishment of cognitive function in the young developing infant oryoung child.

Probiotic may be added to the composition. All probiotic micro-organismsmay be added additionally. Preferably, the probiotic may be selected forthis purpose from the group consisting of Bifidobacterium,Lactobacillus, Lactococcus, Enterococcus, Streptococcus, Kluyveromyces,Saccharoymces, Candida, in particular selected from the group consistingof Bifidobacterium longum, Bifidobacterium lactis, Bifidobacteriumanimalis, Bifidobacterium breve, Bifidobacterium infantis,Bifidobacterium adolescentis, Lactobacillus acidophilus, Lactobacilluscasei, Lactobacillus paracasei, Lactobacillus salivarius, Lactobacilluslactis, Lactobacillus rhamnosus, Lactobacillus johnsonii, Lactobacillusplantarum, Lactobacillus salivarius, Lactococcus lactis, Enterococcusfaecium, Saccharomyces cerevisiae, Saccharomyces boulardii or mixturesthereof, preferably selected from the group consisting ofBifidobacterium longum NCC3001 (ATCC BAA-999), Bifidobacterium longumNCC2705 (CNCM 1-2618), Bifidobacterium longum NCC490 (CNCM 1-2170),Bifidobacterium lactis NCC2818 (CNCM 1-3446), Bifidobacterium brevestrain A, Lactobacillus paracasei NCC2461 (CNCM 1-2116), Lactobacillusjohnsonii NCC533 (CNCM 1-1225), Lactobacillus rhamnosus GG (ATCC53103),Lactobacillus rhamnosus NCC4007 (CGMCC 1.3724), Enterococcus faecium SF68 (NCC2768; NCIMB10415), and mixtures thereof.

In one embodiment the synthetic nutritional compositions of theinvention comprise probiotics active or inactivated, dead or alive,preferably in sufficient dose to be effective (e.g between 10⁶ to 10¹¹or between 10⁷ and 10⁹ cfu/g of composition). In one embodiment thecomposition of the invention for male infant comprises a probiotichaving a specific effect for male infant and is different from theprobiotic comprised in the composition of the invention for femaleinfant. In one embodiment such probiotics comprise Bifidobacteriumlactis or Lactobacillus rhamnosus GG for male and B. Longum for female(or possibly vice-versa). In one embodiment such probiotics compriseBifidobacterium Lactis for male and Lactobacillus Rhamnosus for female(or possibly vice-versa). The choice of probiotics is specificallyadapted for the particular needs of male and female infants.

Generally it starts indeed to be recognized that male and female infantsmay have specific needs (qualitatively and quantitatively) in terms oflipids, oligosaccharides and probiotics.

Vitamins, minerals and other micronutrients suitable for administrationto children under the age of three may be added to the compositions ofthe invention.

The Compositions of the Invention Promote the Healthy Establishment ofCognitive Function:

The nutrients of the compositions of the invention are especiallyassociated with brain maturation, especially the development ofcognitive function in young mammals.

ALA (α-linolenic acid), an omega-3 fatty acid, and LA (linoleic acid),an omega-6 fatty acid, cannot be synthesized by humans and thus must beobtained from the diet. Additionally, two long-chain omega-3 fattyacids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), canbe synthesized from ALA. There are many reports in the literaturesuggesting that these fatty acids may be essential for optimal cognitivefunction development. Among its many roles, DHA influences the functionof the blood-brain barrier, the activity of membrane-bound enzymes andionic channels, dopaminergic and serotoninergic neurotransmission, andsignal transduction [Yaboob, P Annu. Rev. Nutr. 2009.29:257-282].

Ganglioside accretion in the developing brain is highest in utero and inearly neonatal life, during the periods of dendritic branching and newsynapse formation. Further, brain contains the highest relativeganglioside content in the body, particularly in neuronal cell membranesconcentrated in the area of the synaptic membrane. Gangliosides areknown to play a role in neuronal growth, migration and maturation,neuritogenesis, synaptogenesis, and myelination [McJarrow, P., (2009)Nutr. Rev. Aug; 67(8):451-63].

Choline found in phospholipids is the precursor to the neurotransmitteracetylcholine. Loss of cholinergic neurons is associated with impairedcognitive function [Poly et al. (2011) Am. J. Clin. Nutr.,94(6):1584-91].

Sphingomyelin is a type of sphingolipidfound in animal cell membranes,especially in the membranous myelin sheath that surrounds some nervecell axons.

Thus, the compositions according to the invention are especially adaptedto promote the healthy establishment of cognitive function in infantsand young children. By “healthy establishment of cognitive function”, itis meant that the cognitive function of the infant or young child, asmeasured by a standard method, is in the normal range.

Standard methods known to the skilled person are the Bayley Scales ofInfant and Toddler Development® (currently Third Edition (Bayley-III)).This test includes cognitive, language, motor, social-emotional andgeneral adaptive features. Raw scores of successfully completed itemsare converted to scale scores and to composite scores. These scores areused to determine the child's performance compared with norms taken fromtypically developing children of their age (in months). The percentilescores between 85 and 115 are usually accepted as normal cognitivedevelopment [Black M. M. and Matula K. (1999), Essentials of BayleyScales of Infant Development II, Assessment, New York: John Wiley, ISBN978-0-471-32651-9].

Another scale that may be used to measure cognitive function is theGriffiths Scale [Chaudhary T, et al. (2012), Predictive and ConcurrentValidity of Standardized Neurodevelopmental Examinations by theGriffiths Scales and Bayley Scales of Infant Development II., KlinPediatr., December 2012].

According to a preferred embodiment of the invention, the compositionsaccording to the first aspect of the invention and the first compositionin the sets of nutritional compositions according to the third aspect ofthe invention, target male children. According to another preferredembodiment of the invention, the compositions according to the secondaspect of the invention and the second composition in the sets ofnutritional compositions according to the third aspect of the invention,target female children.

In one embodiment of the invention the synthetic nutritional compositionof the invention is an infant formula intended and/or especiallydesigned for preterm infants and/or caesarean-born infants. It isgenerally known, or at least hypothized, that these subject groups aremore prone to suffer from unbalanced nervous system (includingdevelopment thereof) and cognitive development due to the immaturity oftheir metabolic pathways and physiological conditions at birth. Earlyadaptation and control of the diet is therefore of the highestimportance.

In one embodiment of the invention, the synthetic nutritionalcomposition of the invention is an infant formula (or a follow-onformula or a growing up milk or a human milk fortifier), for infantsborn from mothers an history of delivering premature infants or anhistory of malnutrition or an history of lower cognitive development. Itis generally known, or at least hypothized, that these subjects groupsare more prone to suffer from unbalanced nervous system (includingdevelopment thereof) and cognitive development due to the immaturity oftheir metabolic pathways and physiological conditions at birth, due, forexample, to the premature delivery or to genetic or epi-geneticpredispositions. It is, therefore, critical to address such issues asearly as possible during infancy by a specifically adapted diet.

In one embodiment the nutritional compositions of the invention are forinfants that have experienced IUGR, and/or had a low, very low, orextremely low birth weight, is small for gestational age, and/or issuffering or suffered from cognitive function impairment either in uteroor, during, or after birth.

Although the invention has been described by way of example, it shouldbe appreciated that variations and modifications may be made withoutdeparting from the scope of the invention as defined in the claims.Furthermore, where known equivalents exist to specific features, suchequivalents are incorporated as if specifically referred in thisspecification.

EXAMPLES Example 1 Longitudinal Clinical Trial

The present inventors designed a longitudinal clinical trial with 50lactating mothers with milk sampling at 30 (visit 1), 60 (visit 2) and120 (visit 3) days post-partum. The milk samples were quantitativelyanalyzed for energy and total solids.

Human Milk Collection:

The protocol and collection of human milk was reviewed and approved bythe local ethical committee of Singapore. The study took place atNational University of Singapore. Volunteer mothers of term infants, whowere apparently healthy and non-smokers (n=50; 31.1±3.1-year old)provided breast milk samples (approximately 30 mL; 4 weeks post-partum).Samples were collected after full expression from one breast using milkpump and while the baby was fed on the other breast. All efforts weremade to collect complete feed that included fore-milk, mid-milk andhind-milk as a representation of one feed and to avoid within feedvariation of lipid content. Approximately 30 mL aliquot was separated ina conical polypropylene tube for this study and the rest was fed to theinfant. Samples collected for research were stored at −80° C. untilanalyses.

Macronutrient Analysis by Mid-Infrared (MIR) Assay:

The MIR analyses were performed with the Human Milk Analyzer (HMA,Miris, Sweden). The HMA is based on a semisolid MIR transmissionspectroscopy, designed specifically for determination of themacronutrient composition of human milk. The use of the machine wasaccording to manufacturer's instructions. Briefly 1 mL of previouslywarmed sample (up to 40° C. in water bath) was sonicated for 1 minbefore manual injection to the milk inlet. The analysis was conductedwithin next minute before the milk was retrieved and the inlet washedwith de-ionized water. The cell was also washed with supplied detergentevery 5 sample injections. Also every 10 samples an in-house control aswell as calibrating standard provided by Miris were ran for qualitycontrol purposes.

Fatty Acid Analysis:

Fatty acid methyl esters (FAMEs) were prepared using HCl/Methanol (3N)as a catalyst. The methylation procedure was as follows: In a 15 mL testtube equipped with Teflon-lined screw caps, 250 μL of human milk wasadded followed by 300 μL of internal standard FAME 11:0 and 300 μL ofinternal standard TAG 13:0, 2 mL of methanol, 2 mL of methanol/HCL (3N)and 1 mL of n-hexane. Test tubes were firmly capped, shaken vigorouslyand heated at 100° C. for 60 min, with occasional additional shaking.Care was taken to fit the cap tightly with cap liner to avoid leaks whentubes are heated at 100° C. After cooling down to room temperature, 2 mLwater is added and shaken vigorously for centrifugation at 1200 g for 5min followed by the transfer of the upper phase (hexane) into GC vials.For optimal GLC separation, the use of a long (100 m), highly polarcapillary column is recommended. These columns allow accurate separationof FAME, including the cis and trans isomers. GLC analyses wereperformed according to standard conditions known to the skilled person.A 7890A gas-chromatograph with a 7693 autosampler with preparativestation module (Agilent Technologies, Palo Alto, Calif.) equipped with afused-silica CP-Sil 88 capillary column (100% cyanopropylpolysiloxane;100 m, 0.25 mm id, 0.25 μm film thickness; Agilent, Palo Alto, Calif.)was used with a split injector (1:25 ratio) heated at 250° C. and aflame-ionization detector operated at 300° C. The oven temperatureprogramming used was 60° C. isothermal for 5 min, increased to 165° C.at 15° C./min, isothermal for 1 min at this temperature, and thenincreased to 195° C. at 2° C./min and held isothermal for 14 min andthen increased to 215° C. at 5° C./min and held isothermal for 8 min at215° C. Hydrogen was used as carrier gas under constant flow mode at 1.5mL/min.

Phospholipid Analysis: Phospholipid families were separated bynormal-phase high-performance liquid chromatography using 2 Nucleosil50-5, 250×3 mm, 5μ (Macherey-Nagel, Easton, USA) equipped withpre-column Nucleosil 50-5, 8×3 mm, 5μ (Macherey-Nagel, Easton, USA). Thechromatography system consisted of an Agilent 1200 module (AgilentTechnologies, Basel, Switzerland) and an in-line PL-ELS 1000 evaporativelight scattering detector (Polymer Laboratories, Shropshire England).All chromatography was performed at 55° C. Solvent A was composed ofammonium formiate 3 g/L and solvent B of acetonitrile/methanol (100/3v/v). Gradient conditions for phospholipid analysis were as follows:time=0 min 1% solvent A; time=19 min 30% solvent A; time=21 min 30%solvent A; time=24 min 1% solvent A; flow rate was 1 mL/min. Data werecollected and processed using Agilent Chem. Station software.

Ganglioside Analysis: Gangliosides were separated by LC using an AquityBEH C18 column (1.7 μm; 150×2.1 mm i.d.; Waters). The chromatographysystem consisted of Infinity 1290 modules (Agilent Technologies, Basel,Switzerland) coupled to triple quadrupole mass spectrometer (Appliedbiosystems/MSD Sciex, 5500 Ontario, Canada). All chromatography wasperformed at 50° C. Solvent A composed of water/methanol/ammoniumacetate (1 mM) (90/10/0.1 v/v/v) and solvent B of methanol/ammoniumacetate (1 mM) (100/0.1 v/v). Gradient conditions were as follows:time=0 min 10% solvent A; time=0.2 min 10% solvent A; time=8.2 min 5%solvent A; time=12.2 min 5% solvent A; time=12.4 min 0% solvent A;time=18.4 min 0% solvent A; time=18.6 10% solvent A; time=21 10% solventA. Flow rate was 0.2 mL/min. The mass spectrometer was equipped withelectrospray ionization (ESI) ion source. The ESI mass spectra wererecorded in the negative ion mode under the following conditions: ionspray voltage (IS) −4000 V, temperature of the source 250° C.,declustering potential (DP) −40V. Disialogangliosides 3 (GD3) andmonosialogangliosides 3 (GM3), were monitored by transitions of theprecursor ions to the m/z 290 product ion listed in the Table 1. The ionm/z 290 corresponds to Neu5Ac fragments obtained from B type of cleavageaccording to (13). Data were collected and processed using Multiquantsoftware 2.1 (Applied Biosystems, Sciex, Ontario, Canada).Quantification was performed by calibration curve. Stock solutions ofGD3 and GM3 were prepared in methanol 70% (1 mg/mL) and furtherdilutions to volume with methanol 70% were performed to give 6concentration levels covering a range from 7.5 to 22.5 μg/mL. Total areaof GD3 and GM3 was calculated as the sums of peak areas of thetransitions of the precursor ions to the m/z 290 product ion.

Statistical Analysis:

Data collection points are 1, 2 and 4 months after infants' birth. Table2 shows the Min, Mean, SD and Max for each unit of measurementStatistical models fitted to the raw data are shown in FIGS. 1-3.Longitudinal analysis was carried out using linear mixed models. Thefigures also show the sequential effect of each of the terms age, age²,gender and age-gender interactions in this particular order in terms ofthe P-value for the corresponding F-test. Thus, the P[age] is a P valueconsidering a linear model and P[age²] corresponds to a quadratic one.The appropriate model is chosen according to whether the trajectory islinear (P[age]) or curved (P[age²]).

Adjusted R-squares were computed to obtain the degree of variabilitythat is explained by the statistical models used.

Analysis was carried out using the following mixed-effects linear model:

Conc: =Age+Age²+Gender+Age_Gender+(Age²)_Gender+Random Effects:

Random effects are subject specific terms to model the underlyingcorrelation between repeat measures.

TABLE 1 Precursor ions for GD3 and GM3. The collision energy (CE) wasset at −40 V. Type of Predicted Observed Mass Error Assigned molecularion m/z m/z (ppm) structure [M − H]⁻ 1125.6897 1125.6902 8.7 GM3d32:0 [M− H]⁻ 1151.7053 1151.7059 −5.1 GM3d34:1 [M − H]⁻ 1149.6897 1149.6002 8.5GM3d34:2 [M − H]⁻ 1175.7053 1175.7059 5.0 GM3d36:3 [M − H]⁻ 1173.68691173.6902 8.3 GM3d36:4 [M − H]⁻ 1207.7679 1207.7685 1.3 GM3d38:1 [M −H]⁻ 1235.7992 1235.7998 0.2 GM3d40:1 [M − H]⁻ 1223.7992 1223.7998 0.2GM3d40:7 [M − H]⁻ 1263.8305 na — GM3d42:1 [M − H]⁻ 1261.8149 na —GM3d42:2 [M − 2H]²⁻  706.8808  706.8814 −1.9 GD3d32:1 [M − 2H]²⁻ 721.9043  721.9048 −6.7 GD3d34:0 [M − 2H]²⁻  720.8965  720.8970 4.1GD3d34:1 [M − 2H]²⁻  719.8887  719.8892 0.2 GD3d34:2 [M − 2H]²⁻ 718.8808  718.8814 −1.9 GD3d34:3 [M − 2H]²⁻  728.9121  728.9127 −3.7GD3d35:0 [M − 2H]²⁻  735.9195  735.9205 0.5 GD3d36:0 [M − 2H]²⁻ 733.9043  733.9048 −6.6 GD3d36:2 [M − 2H]²⁻  742.9278  742.9283 2.3GD3d37:0 [M − 2H]²⁻  741.9200  741.9205 −0.7 GD3d37:1 [M − 2H]²⁻ 749.9356  749.8984 2.1 GD3d38:0 [M − 2H]²⁻  747.9200  747.9205 0.7GD3d38:2 [M − 2H]²⁻  746.9121  746.9127 −3.6 GD3d38:3 [M − 2H]²⁻ 745.9043  745.9048 6.5 GD3d38:4 [M − 2H]²⁻  744.8965  744.8970 −9.4GD3d38:5 [M − 2H]²⁻  743.8887  743.8892 1.1 GD3d38:6 [M − 2H]²⁻ 763.9513  763.9528 −2.3 GD3d40:0 [M − 2H]²⁻  762.9434  762.9440 −5.2GD3d40:1 [M − 2H]²⁻  777.9669  777.9674 3.3 GD3d42:0 [M − 2H]²⁻ 775.9513  775.9048 −6.2 GD3d42:2 nd: not detected na: identification byhigh mass resolution mass spectrometer was not possible because outsidethe capability m/z range of the instrument.

TABLE 2 Longitudinal evolution of energy value and various lipids inhuman milk secreted for baby girls (N = 25) and baby boys (N = 25) Milksecreted for baby girls Milk secreted for baby boys Combined NutrientVisit Min Mean SD max Min Mean SD max Min Mean SD max Linoleic acid V139.67 461.57 191.76 848.29 27.01 670.57 256.17 1294.82 27.01 566.07247.58 1294.82 (mg per 100 V2 65.55 508.30 274.10 1344.37 179.15 670.45336.10 1343.89 65.55 589.37 314.38 1344.37 mL) V3 16.79 526.20 418.801864.30 236.95 730.90 422.92 1844.22 16.79 628.55 429.02 1864.30α-Linolenic V1 5.16 32.96 21.61 89.74 17.92 47.12 22.28 109.00 5.1640.04 22.87 109.00 acid (mg V2 2.56 40.76 29.44 124.72 7.45 41.90 29.91154.67 2.46 41.33 29.38 154.67 per 100 mL) V3 0.72 30.80 25.55 125.9311.21 45.29 26.12 123.80 0.72 38.05 26.59 125.93 Total PUFA V1 0.12 0.570.22 0.96 0.22 0.80 0.27 1.46 0.12 0.68 0.27 1.46 Acids (g per V2 0.080.60 0.32 1.57 0.22 0.78 0.38 1.57 0.08 0.69 0.36 1.57 100 mL) V3 0.020.61 0.49 2.21 0.29 0.84 0.48 2.18 0.02 0.73 0.49 2.21 GM3 (mg V1 0.080.25 0.09 0.45 0.11 0.22 0.07 0.41 0.08 0.23 0.08 0.45 per 100 mL) V20.11 0.27 0.12 0.59 0.13 0.30 0.15 0.65 0.11 0.29 0.14 0.65 V3 0.01 0.350.16 0.60 0.16 0.43 0.20 0.89 0.01 0.39 0.18 0.89 GM3 + GD3 V1 0.29 0.480.19 1.07 0.21 0.45 0.10 0.60 0.21 0.46 0.15 1.07 (mg per 100 V2 0.180.47 0.27 1.37 0.17 0.48 0.19 0.90 0.17 0.47 0.23 1.37 mL) V3 0.06 0.480.18 0.90 0.25 0.62 0.32 1.49 0.06 0.55 0.27 1.49 Sphingo- V1 5.42 8.071.32 10.57 4.84 8.86 1.99 12.65 4.84 8.47 1.72 12.65 myelin (mg V2 2.456.93 2.42 13.74 3.38 8.49 3.37 17.74 2.45 7.71 3.01 17.74 per 100 mL) V33.99 7.89 2.72 13.73 5.51 9.37 2.40 14.15 3.99 8.66 2.64 14.15Phosphatidyl- V1 3.31 5.81 1.26 8.30 3.29 6.12 1.42 9.23 3.29 5.97 1.349.23 choline (mg V2 1.62 4.43 1.89 8.70 1.96 5.25 2.17 11.92 1.62 4.842.06 11.92 per 100 mL) V3 1.97 4.52 1.98 8.44 3.24 5.32 1.72 10.16 1.974.94 1.88 10.16 Phosphatidyl- V1 3.15 6.47 1.62 9.04 3.19 7.05 2.0611.12 3.15 6.76 1.86 11.12 ethanolamine V2 2.35 5.70 2.30 11.15 2.377.02 3.68 18.25 2.35 6.36 3.11 18.25 (mg per 100 V3 2.67 7.24 3.23 14.715.26 8.85 2.81 15.38 2.67 8.08 3.10 15.38 mL) Phos- V1 0.54 0.99 0.271.57 0.59 1.15 0.41 2.25 0.54 1.07 0.35 2.25 phatidylinositol V2 0.471.00 0.38 2.01 0.41 1.27 0.66 2.70 0.41 1.13 0.55 2.70 (mg per 100 mL)V3 0.64 1.51 0.66 3.88 1.01 1.81 0.63 3.14 0.64 1.67 0.66 3.88Phosphatidyl- V1 0.35 0.66 0.14 0.93 0.27 0.85 0.39 1.93 0.27 0.75 0.311.93 serine (mg V2 0.35 0.70 0.30 1.71 0.40 0.80 0.35 1.57 0.35 0.750.33 1.71 per 100 mL) V3 0.39 0.86 0.37 1.93 0.54 0.94 0.29 1.48 0.390.91 0.33 1.93 Total V1 14.16 22.01 1.41 28.59 12.54 24.03 5.42 33.7712.54 23.02 4.88 33.77 phospholipid V2 7.64 18.73 6.67 31.93 8.61 22.839.76 51.67 7.64 20.78 8.53 51.67 content (mg V3 9.72 22.02 8.63 41.8815.66 26.29 7.44 42.95 9.72 24.24 8.23 42.95 per 100 mL)

Example 2

An example of a starter infant formula for infant boys up to the age ofthree months is given below. The protein source is a conventional mix ofwhey protein and casein.

Nutrient per 100 kcal per litre Energy (kcal) 100 678 Protein (g) 1.6811.3 Fat (g) 6.38 43.64 Linoleic acid (g) 0.98 6.7 α-Linolenic acid (mg)70 471 Lactose (g) 9.41 62.6 Minerals (g) 0.37 2.5 Na (mg) 23 150 K (mg)89 590 Cl (mg) 64 430 Ca (mg) 62 410 P (mg) 31 210 Mg (mg) 7 50 Mn (μg)8 50 Se (μg) 2 13 Vitamin A (μg RE) 105 700 Vitamin D (μg) 1.5 10Vitamin E (mg TE) 0.8 5.4 Vitamin K1 (μg) 8 54 Vitamin C (mg) 10 67Vitamin B1 (mg) 0.07 0.47 Vitamin B2 (mg) 0.15 1 Niacin (mg) 1 6.7Vitamin B6 (mg) 0.075 0.5 Folic acid (μg) 9 60 Pantothenic acid (mg)0.45 3 Vitamin B12 (μg) 0.3 2 Biotin (μg) 2.2 15 Choline (mg) 10 67 Fe(mg) 1.2 8 I (μg) 15 100 Cu (mg) 0.06 0.4 Zn (mg) 0.75 5 GM3 (mg) 0.322.2 GD3 (mg) 0.34 2.3 Sphingomyelin (mg) 13.16 88.6 Phosphatidylcholine(mg) 9.12 61.2 Phosphatidylethanolamine 10.51 70.5 (mg)Phosphatidylinositol (mg) 1.75 11.5 Phosphatidylserine (mg) 1.3 8.5

Example 3

An example of a starter infant formula for infant boys older than threemonths is given below. The protein source is a conventional mix of wheyprotein and casein.

Nutrient per 100 kcal per litre Energy (kcal) 100 775.64 Protein (g)1.18 8.48 Fat (g) 6.73 53.88 Linoleic acid (g) 0.92 7.31 α-Linolenicacid (mg) 60 452.9 Lactose (g) 8.64 63.56 Minerals (g) 0.37 2.5 Na (mg)23 150 K (mg) 89 590 Cl (mg) 64 430 Ca (mg) 62 410 P (mg) 31 210 Mg (mg)7 50 Mn (μg) 8 50 Se (μg) 2 13 Vitamin A (μg RE) 105 700 Vitamin D (μg)1.5 10 Vitamin E (mg TE) 0.8 5.4 Vitamin K1 (μg) 8 54 Vitamin C (mg) 1067 Vitamin B1 (mg) 0.07 0.47 Vitamin B2 (mg) 0.15 1 Niacin (mg) 1 6.7Vitamin B6 (mg) 0.075 0.5 Folic acid (μg) 9 60 Pantothenic acid (mg)0.45 3 Vitamin B12 (μg) 0.3 2 Biotin (μg) 2.2 15 Choline (mg) 10 67 Fe(mg) 1.2 8 I (μg) 15 100 Cu (mg) 0.06 0.4 Zn (mg) 0.75 5 GM3 (mg) 0.564.3 GD3 (mg) 0.3 2 Sphingomyelin (mg) Phosphatidylcholine (mg) 7.07 53.2Phosphatidylethanolamine 11.83 88.5 (mg) Phosphatidylinositol (mg) 2.418.1 Phosphatidylserine (mg) 1.28 9.4

Example 4

An example of a starter infant formula for infant girls up to threemonths is given below. The protein source is a conventional mix of wheyprotein and casein.

Nutrient per 100 kcal per litre Energy (kcal) 100 640.4 Protein (g) 1.6610.72 Fat (g) 6.18 39.8 Linoleic acid (g) 0.72 4.62 α-Linolenic acid(mg) 50 329.6 Lactose (g) 9.98 62.88 Minerals (g) 0.37 2.5 Na (mg) 23150 K (mg) 89 590 Cl (mg) 64 430 Ca (mg) 62 410 P (mg) 31 210 Mg (mg) 750 Mn (μg) 8 50 Se (μg) 2 13 Vitamin A (μg RE) 105 700 Vitamin D (μg)1.5 10 Vitamin E (mg TE) 0.8 5.4 Vitamin K1 (μg) 8 54 Vitamin C (mg) 1067 Vitamin B1 (mg) 0.07 0.47 Vitamin B2 (mg) 0.15 1 Niacin (mg) 1 6.7Vitamin B6 (mg) 0.075 0.5 Folic acid (μg) 9 60 Pantothenic acid (mg)0.45 3 Vitamin B12 (μg) 0.3 2 Biotin (μg) 2.2 15 Choline (mg) 10 67 Fe(mg) 1.2 8 I (μg) 15 100 Cu (mg) 0.06 0.4 Zn (mg) 0.75 5 GM3 (mg) 0.382.5 GD3 (mg) 0.33 2.3 Sphingomyelin (mg) 12.71 80.7 Phosphatidylcholine(mg) 9.16 58.1 Phosphatidylethanolamine 10.16 64.7 (mg)Phosphatidylinositol (mg) 1.58 9.9 Phosphatidylserine (mg) 1.04 6.6

Example 5

An example of a starter infant formula for infant girls older than threemonths is given below. The protein source is a conventional mix of wheyprotein and casein.

Nutrient per 100 kcal per litre Energy (kcal) 100 626.17 Protein (g) 1.48.12 Fat (g) 5.87 38.75 Linoleic acid (g) 0.82 5.26 α-Linolenic acid(mg) 50 308 Lactose (g) 10.35 65.38 Minerals (g) 0.37 2.5 Na (mg) 23 150K (mg) 89 590 Cl (mg) 64 430 Ca (mg) 62 410 P (mg) 31 210 Mg (mg) 7 50Mn (μg) 8 50 Se (μg) 2 13 Vitamin A (μg RE) 105 700 Vitamin D (μg) 1.510 Vitamin E (mg TE) 0.8 5.4 Vitamin K1 (μg) 8 54 Vitamin C (mg) 10 67Vitamin B1 (mg) 0.07 0.47 Vitamin B2 (mg) 0.15 1 Niacin (mg) 1 6.7Vitamin B6 (mg) 0.075 0.5 Folic acid (μg) 9 60 Pantothenic acid (mg)0.45 3 Vitamin B12 (μg) 0.3 2 Biotin (μg) 2.2 15 Choline (mg) 10 67 Fe(mg) 1.2 8 I (μg) 15 100 Cu (mg) 0.06 0.4 Zn (mg) 0.75 5 GM3 (mg) 0.563.5 GD3 (mg) 0.25 1.3 Sphingomyelin (mg) 11.92 78.9 Phosphatidylcholine(mg) 6.68 45.2 Phosphatidylethanolamine 10.68 72.4 (mg)Phosphatidylinositol (mg) 2.28 15.1 Phosphatidylserine (mg) 1.31 8.6

Example 6

An example of the composition of a hypoallergenic (HA) starter infantformula for infant girls according to the present invention is givenbelow. This composition is given by way of illustration only. Theprotein source is a conventional mix of whey protein and casein.

Nutrient per 100 kcal per litre Energy (kcal) 100 670 Partiallyhydroylsed 1.83 12.3 protein (g) Fat (g) 5.3 35.7 Linoleic acid (g) 4.9α-Linolenic acid (mg) 275 Lactose (g) 11.2 74.7 Prebiotic (100% GOS) (g)0.64 4.3 Minerals (g) 0.37 2.5 Na (mg) 23 150 K (mg) 89 590 Cl (mg) 64430 Ca (mg) 62 410 P (mg) 31 210 Mg (mg) 7 50 Mn (μg) 8 50 Se (μg) 2 13Vitamin A (μg RE) 105 700 Vitamin D (μg) 1.5 10 Vitamin E (mg TE) 0.85.4 Vitamin K1 (μg) 8 54 Vitamin C (mg) 10 67 Vitamin B1 (mg) 0.07 0.47Vitamin B2 (mg) 0.15 1.0 Niacin (mg) 1 6.7 Vitamin B6 (mg) 0.075 0.50Folic acid (μg) 9 60 Pantothenic acid (mg) 0.45 3 Vitamin B12 (μg) 0.3 2Biotin (μg) 2.2 15 Choline (mg) 10 67 Fe (mg) 1.2 8 I (μg) 15 100 Cu(mg) 0.06 0.4 Zn (mg) 0.75 5 GM3 (mg) 3.1 GD3 (mg) 1.9 Sphingomyelin(mg) 88 Phosphatidylcholine (mg) 57 Phosphatidylethanolamine 69 (mg)Phosphatidylinositol (mg) 12 Phosphatidylserine (mg) 7.5

1. A synthetic nutritional composition for infants or young childrencomprising: 600-810 mg/100 ml linoleic acid; 42-52 mg/100 ml α-linolenicacid; and 720-920 mg/100 ml total polyunsaturated fatty acids, whereinthe composition is especially adapted to the nutritional needs of a maleinfant or child.
 2. The synthetic nutritional composition of claim 1,wherein the composition also comprises a component selected from thegroup consisting of: 0.18-0.50 mg/100 ml of GM3; 0.4-0.7 mg/100 ml ofGM3+GD3; and 8.0-10.4 mg/100 ml of sphingomyelin.
 3. The syntheticnutritional composition according to claim 1, wherein the compositionalso comprises a phospholipid selected from the group consisting of:4.7-5.9 mg/100 ml of phosphatidylcholine; 6.3-10 mg/100 ml ofphosphatidylethanolamine; 1-2 mg/100 ml of phosphatidylinositol; and0.7-1.1 mg/100 ml of phosphatidylserine.
 4. The synthetic nutritionalcomposition according to claim 1, wherein the composition comprises: 20to 30 mg/100 ml of phospholipids.
 5. A synthetic nutritional compositionfor infants or young children comprising: 410-580 mg/100 ml linoleicacid; 26-30 mg/100 ml α-linolenic acid; and 510-680 mg/100 ml totalpolyunsaturated fatty acids, wherein the composition is especiallyadapted to the nutritional needs of a female infant or child.
 6. Thesynthetic nutritional composition of claim 5, wherein the compositionalso comprises a component selected from the group consisting of:0.22-0.40 mg/100 ml of GM3; 0.4-0.6 mg/100 ml of GM3+GD3; and 7-9 mg/100ml of sphingomyelin.
 7. The synthetic nutritional composition of claim5, wherein the composition also comprises a phospholipid selected fromthe group consisting of: 5-6.4 mg/100 ml of phosphatidylcholine; 5.8-8mg/100 ml of phosphatidylethanolamine; 0.8-1.7 mg/100 ml ofphosphatidylinositol; and 0.5-1 mg/100 ml of phosphatidylserine.
 8. Thesynthetic nutritional composition according to claim 5, wherein thecomposition comprises: 19.5 to 25 mg/100 ml of phospholipids. 9.(canceled)
 10. A set of synthetic nutritional compositions for infantsor young children, comprising: a first composition comprising 600-810mg/100 ml linoleic acid; 42-52 mg/100 ml α-linolenic acid; and 720-920mg/100 ml total polyunsaturated fatty acids; and a second compositioncomprising 410-580 mg/100 ml linoleic acid; 26-30 mg/100 ml α-linolenicacid; and 510-680 mg/100 ml total polyunsaturated fatty acids, whereinthe first composition is especially adapted to the nutritional needs ofa male infant or child and the second composition is especially adaptedto the nutritional needs of a female infant or child.
 11. A method forpromoting the healthy establishment of cognitive function in maleinfants and young children comprising the step of administering asynthetic nutritional composition comprising: 600-810 mg/100 ml linoleicacid; 42-52 mg/100 ml α-linolenic acid; and 720-920 mg/100 ml totalpolyunsaturated fatty acids.
 12. A method for promoting the healthyestablishment of cognitive function in female infants and young childrencomprising the step of administering a synthetic nutritional compositioncomprising: 410-580 mg/100 ml linoleic acid; 26-30 mg/100 ml α-linolenicacid; and 510-680 mg/100 ml total polyunsaturated fatty acids.
 13. Amethod for promoting the healthy establishment of cognitive function ininfants and young children, comprising: administering a firstcomposition comprising 600-810 mg/100 ml linoleic acid; 42-52 mg/100 mlα-linolenic acid; and 720-920 mg/100 ml total polyunsaturated fattyacids, to male infants or young children; and administering a secondcomposition comprising 410-580 mg/100 ml linoleic acid; 26-30 mg/100 mlα-linolenic acid; and 510-680 mg/100 ml total polyunsaturated fattyacids, is administered to female infants or young children.
 14. Thesynthetic nutritional compositions according to claim 1, wherein thecomposition is in a form selected from the group consisting of an infantformula in the form of a powder, liquid or concentrated liquid, and ahuman milk fortifier.
 15. The set of synthetic nutritional compositionsaccording to claim 10, wherein the first or second composition areindependently an infant formula in the form of a powder, liquid orconcentrated liquid, or is a human milk fortifier.
 16. The method ofclaim 11, wherein cognitive function is measured according to standardscales, such as Griffiths Scales or Bayley Scales.
 17. (canceled) 18.The synthetic nutritional compositions according to claim 5, wherein thecomposition is in a form selected from the group consisting of an infantformula in the form of a powder, liquid or concentrated liquid, and ahuman milk fortifier.
 19. The method of claim 12, wherein cognitivefunction is measured according to standard scales, such as GriffithsScales or Bayley Scales.